Behydro-emehnes



United States Patent O 3,311,633 Z-DEHYDRG-EMETINES Arnold Brossi,Verona, N.J., assignor to Hotimann-La Roche Inc., Nutley, NJ., acorporation of New Jersey No Drawing. Filed Mar. 19, 1963, Ser. No.266,183 Claims priority, application Switzeriand, Mar. 21, 1962, 3,386/62 2 Claims. (Cl. 260-288) The present invention relates topharmaceutically useful novel compounds and methods for theirpreparation. More specifically, the present invention relates to (-)-2-dehydro-emetine and its 3-lower alkyl homologs. The present inventionalso relates to a method of preparing these specific optically activecompounds, which method comprises using an optically active compound,i.e., a ()-benzo[a] quinolizine, as a starting material, and whichmethod preserves the optical specificity, thus providing a facile routeto the desired optically active end products.

Z-dehydro-emetine, which is an outstanding chemotherapeutic for thetreatment of amebiasis and bilharziasis, possesses two asymmetric carbonatoms and is obtained according to known methods in the form of aracemate. It has now been found that from the racemic form, which, forexample, consists of equal parts of compounds of Formulas Ia and Ilashown below, only the ()-2-dehydro-emetine Ia exhibits the desiredchemotherapeutic characteristics, whereas the (-]-)-2-dehydroemetine Hais inactive.

used herein, lower alkyl refers to both straight and branched chainhydrocarbon groups such as methyl, ethyl, propyl, isopropyl, butyl,isobutyl and the like. More specifically, when R is ethyl, the compoundsrepresent Z-dehydro-emetine and are referred to as Ia and Ila,respectively. Wherein R represents a lower alkyl moiety 'ice other thanethyl, the compounds will be referred to as Ib and 11b, respectively.

In view of the above finding of chemotherapeutic activity beingcritically dependent on the optical configuration, a stereo-specificsynthesis of the active isomer is of great interest. Such a method forthe synthesis of Z-dehydro-emetine Ia, and its 3-lower alkyl homologsIb, is the subject of this invention.

A known method for the preparation of rac. Z-dehydroemetine consists ofcondensing homoveratrylamine with rac. 2carbalkoXymethyl-3-ethyl-9,10-dimethoXy-1,4,6,7- tetrahydro-llbH-benzo[a] quinolizine, or the product obtained via the hydrolysisthereof, i.e., 2-carboXymethyl-3- ethyl-9,10-dimethoXy-1,4,6,7tetrahydro llbH-benzo- [a]quinolizine, cyclizing the so-formed acidamide and hydrogenating the thus obtained Z-dehydro 0 methylpsychotrine.Proceeding from substituted benzo[-a] quinolizines containing, insteadof the ethyl group in the 3- position, for example, a methyl, propyl,isopropyl, butyl, or isobutyl group, there are obtained 3-lower alkylhomologs of Z-dehydro-emetine.

One embodiment of the present invention is a method for the preparationof (-)-2-dehydro-emetine Ia and its 3-alkyl homologs lb which comprisesbeginning with ()-2 carb lower alkoxy methyl 3 lower alkyl- 9,10,dirnethoxy 1,4,6,7 tetrahydro llbH benzo- [a]quinolizine (Formula III)as a starting material.

2 carb lower alkoxymethyl 3 lower alkyl- 9,l0 dimethoxy 1,4,6,7tetrahydro llbI-I benzo- [a]quinolizine Ila can be advantageouslyprepared by separation of me. Z-carb-lower alkoxymethyl-3-loweralkyl-9,10-dimethoxy 1,4,6,7 tetrahydro 1'1bH-benzo- [a]quinolizine intoits optical antipodes Illa and Na. This separation can be effected, forexample, via fractional crystallization of the salts formed between theracemate and a suitable optically active acid such asdibenzoyl-D-tartaric acid, L-tartaric acid, etc. A preferred method forthe preparation of 1110 from the racemate consists of addingdibenzoyl-D-tartaric acid to said racemate and then separating thedibenzoyl-D-tar trate of IVc. From the filtrate, 1110 is then obtainedvia concentration, followed by decomposition with alk-ali. Said IIIc canthen be purified via the L-tartrate.

The (-)-rotatory enantiomeric base 111:! in the next phase of thedescribed reaction sequence undergoes acid amide formation, cyclizationand hydrogenation. The (-|)-rotatory enantiomeric base IVa can again bereconverted into the racemic form and this can, once again, be separatedinto its optical antipodes. By this procedure, the total yield of thedesired end product is elevated. One such method for reconverting thenondesired (+)-antipode into the racemate is an object of the instantinvention. The conversion into the racemate can, for example, beeffected by oxidizing IVa with mercuric, cupric or ferric salt,advantageously with mercuric acetate in acetic acid solution, to aZ-carb-lower alkoxymethyl 3 lower alkyl 9,10 dimethoxydihydro-llbH-benzo[a]quinolizine which subsequently can be reduced.

The compounds formed by oxidation can be represented by Formula V below,when present in the form of the respective bases, whereas, when presentas quaternary salts, they are represented by Formula VI:

1 CH CH:

R=R'=lower alkyl X=anion, e.g. halogen ion As becomes evident from theabove Formulae V and VI, tautomerism is involved.

The subsequent reduction can be effected by suitable reduction systems,for example, potassium borohydride or sodium 'borohydride in a loweralkanol such as methanol. The reduction can also be effected bycatalytichydrogenation, for example, in the presence of platinum oxide.

Preliminary to the formation of the homoveratrylamide, the carb-loweralkoxymethyl compound IIIa is advantageously saponified to thecarboxymethyl compound IIIb, which saponification can be affected viaacid hydrolysis, for example, via boiling with dilute mineral acid suchas dilute hydrochloric acid. The acid amide formation (i.e. theformation of the homoveratrylamide) and the cyclization to()-2-dehydro-O-methylpsychotrine or its 3-alkyl homologs can be effectedaccording to methods known per se. The hcrnoveratrylamide is formed, forexample, by the heating of IIIb with homoveratrylamine in an inertorganic water immiscible solvent, preferably an aromatic hydrocarbon,such as benzene, toluene or xylene, in the course of which the aqueousazeotrope formed is removed. The cyclization is suitably effected by theintroduction into the reaction mixture of a phosphorus cyclization agentsuch as phosphorus oxychloride, phosphorus pentoxide or the like, in aninert solvent, such as benzene, and at an elevated temperature, forexample, at the boiling point of the reaction mixture.

The subsequent hydrogenation (i.e. reduction) of the cyclized productproceeds via formation of a new asymmetric center at the carbon atom 1of the isoquinoline ring to a stereoisomeric mixture consisting of I andVII.

(VII) The hydrogenation can be effected, for example, catalytically orby means of an alkali metal-metal hydride such as lithium borohydride,lithium aluminum hydride, sodium borohydride or the like. In the case ofthe reduction of ()-2-dehydro-O-methyl-psychotrine there is obtained,beside the desired ()-2-dehydro-emetine la also ()-2- dehydro-isoemetineVIIa.

The compounds of the ()-2dehydro-isoemetine series can be separated, forexample, via fractional crystallization, from the compounds of the()-2-dehydro-emetine series. The separation can be effected, forexample, via fractional crystallization of the mineral acid salts, suchas the hydrohalide salts, for example, the dihydrochloride,dihydrobromide, etc.

In a further reaction step, the non-desired compounds of the()-2-dehydro-isoemetine-series, for example VlIa, can be reconvertedinto the desired isomer. This can be effected by first dehydrogenatingto eliminate the asymmetric center found in the 1'-position, thusforming a compound of the ()-2-dehydro-O-methyl-psychotrine series,

7 and by subsequently hydrogenating to form a stereoisomeric mixture Iand VII. The dehydrogenation can b effected, for example, viaN-halogenation of the nitrogen atom of the isoquinoline ring, followedby subsequent treatment with an alkaline agent.

The ()-2-dehydro-emetine and its 3-a1kyl homologs of Formula I obtainedaccording to the processes of this invention, are new compounds withvaluable chemothera peutic properties, for example amebicidalproperties; and therefore useful as chemotherapeutic's in the treatmentof amebiasis. Said compounds of Formula I are basic in nature and formacid addition salts of both organic and inorganic acids. Thus they formpharmaceutically ac ceptable acid addition salts with medicinallyacceptable acids such as hydrohalic acids, for example, hydrochloricacid, hydrobromic acid, nitric acid, sulfuric acid, phos phoric acid,p-toluene sulfonic acid, and the like. They can be used, for example, inthe form of conventional pharmaceutical preparations in which either abase of Formula I or a pharmaceutically acceptable acid addition saltthereof can be incorporated; for example, said active agent can beemployed in combination with pharmaceutical organic or inorganic inertcarrier materials suitable for enteral or parenteral application, forexample water, gelatin, starch, magnesium stearate, talc, vegetableoils, gums, polyalkylene glycols, Vaseline and the like. Thepharmaceutical preparations can be in conventional solid forms such astablets, drages, suppositories, capsules, etc.; or in conventionalliquid forms such as solutions, suspensions or emulsions. They can besubjected to conventional pharmaceutical procedures, for example,sterilization, and can contain conventional pharmaceutical excipients oradjuvants, for example, preservatives, wetting agents, emulsifyingagents, salts for the adjustment of osmotic pressure, or buffers. Theycan also contain other chemotherapeutic agents.

The following examples are illustrative, but not limita- 3 tive, of theinvention. All temperatures are stated in degrees centigrade.

EXAMPLE 1 82 g. of2-carbomethoxymethyl-3-ethyl-9,IO-dimethoxy-l,4,6,7-tetrahydro-11bH-benzo[a]quinolizinewas dissolved in 100 ml. of methanol. To this solution there was thengradually added with stirring, a solution of 90 g. ofdibenzoyl-D-tartrate acid in 100 ml. of methanol. Ether was then addedto the reaction mixture until turbidity, the mixture then permitted tostand for 2 hours in the cold, and the filtrate then separated from theprecipitated crystals (the filtrate, as described in the next paragraph,was worked up to the ()-base). Upon crystallization of the precipitatefrom 300 ml. of methanol there was obtained 63 g. of adibenzoyl-D-tartrate which melted at 137148; [a] :+49 (c.=1 inmethanol). In order to obtain the free base, 58 g. of thisdibenzoyl-D-tartrate was partitioned between ether and dilute aqueoussodium hydroxide; after which the ether solution was separated, driedand concentrated. The residue consisted of 30 g. of(+)-2-carbomethoxymethyl- 3 ethyl9,10-dimethoxy-1,4,6,7-tetrahydro-1lbH-benzo [a]quinolizine in the formof an oil. A fraction distilled off in a high vacuum of 0.05 mm. Hg andat a bath temperature of 230 exhibited an optical rotation of [a] =+249(c.:2.2 in methanol).

In order to isolate the ()-antipode, the above mentioned filtrate wasconcentrated to dryness and the residue partitioned between diluteaqueous sodium hydroxide and ether, and the ether solution separated andconcentrated. The so-obtained residue was dissolved in 250 ml. ofacetone, and 23 g. of finely pulverized tartaric acid added thereto. Themixture was then warmed until complete solution was etfected. Thesolution was then permitted to stand overnight, whereupon an L-tartratesalt crystallized out and was filtered ofi', then recrystallized frommethanol/ether yielding 50 g. of an L-tartrate, melting at 103105, [a]=-150 (c.=1 in methanol). In order to isolate the ()-base, 45 g. of thisL-tartrate was partitioned between sodium hydroxide and ether. The ethersolution was then dried and concentrated, yielding 30 g. of(--)-2-carbomethoxymethyl-3ethyl-9,10-dimethoxy-1,4,6,7-tetrahydro-1lbH-benzo[a]quinolizinein the form of an oil. A sample obtained by distillation in a highvacuum at 0.01 mm. Hg and at a bath temperature of 230 exhibited anoptical rotation of [cc] =255 (c.=2 in methanol).

30 g. of ()-2-carbomethoxymethyl-3-ethyl-9,10-dimethoxy 1,4,6,7tetrahydro-llbH-benzo[a]quinolizine was dissolved in 500 ml. of 3 Nhydrochloric acid and the resulting mixture boiled for one hour atreflux, then concentrated in a water jet vacuum and the residuedissolved in sodium hydroxide. The ether soluble part was then removedvia extraction with ether and the sodium hydroxide phase adjusted to pH6.5 by addition of acetic acid. Solid sodium chloride was then addedthereto until saturation, and the mixture then extracted withchloroform. The combined chloroform phases were concentrated and theresidue dissolved in ethyl acetate. The ethyl acetate solution waspartially concentrated and then permitted to stand until crystallizationoccurred. There was obtained by this method, 23 g. of(-)-2-carboxymethyl 3-ethyl-9,10-dimethoxy-1,4,6,7-tetrahydro-1lbH-benzo[a] quinolizine melting at 141-143 (c.=1 in methanol).

22 g. of the latter substance was then suspended in 200 ml. of xylene,22 g. of homoveratrylamide added thereto and the reaction mixture heatedat reflux for 16 hours, during which the water formed was withdrawn fromthe reaction mixture via azeotropic distillation. The reaction mixturewas then concentrated in vacuo and the residue treated with ether untilcrystallization occurred. The so-formed mixture was then filtered oh?and crystallized from ethyl acetate yielding 26 g. of the(-)-homoveratrylamide of2-carboxymethyl-3-ethyl-9,lO-dimethoxy-1,4,6,7-tetrahydr0-l lbH-benzo[a]quinolizine melting at 155-157"; [a] =189 (c.=l in methanol). 25 g. ofthe so-obtained (-)-homoveratrylamide was dissolved in 260 ml. ofbenzene and 12 ml. of phosphorus oxychloride added to this solution. Themixture was then warmed for 1 hour at and subsequently concentrated invacuo, the residue dissolved in water, the aqueous phase renderedalkaline via addition of dilute sodium hydroxide and the free base thenextracted with ethyl acetate. The ethyl acetate solution was then driedand concentrated and the residue dissolved in acetone. Methanolichydrochloric acid was then added thereto, and the resulting mixturediluted with ether until turbidity sets in. After being permitted tostand, the resulting crystals were filtered off and recrystallized frommethanol/ether (:10), yielding 12 g. of ()-2-dehydro-O-methyl-psychotrine-dihydrochloride in the form of a hydrate with 3%.moles of water of crystallization, which hydrate was in the form of areddish brown product which melted at 178180; [a] (c.=1 in water).U.V.-absorption maxima at 235, 289, 305 and 359 m e=17,700, 8,500, 8,900and 8,200 (in ethanol).

9 g. of the free base obtained from the above dihydrochloride viatreatment with ammonia solution and the customary work up, was dissolvedin 100 ml. of methanol and treated portionwise with 2 g. of sodiumborohydride. After standing for 12 hours it was dried, the residuepartitioned between water and ether, and the ether solution separatedand concentrated. The basic mixture was then taken up in aqueoushydrobromic acid and permitted to stand, whereupon there crystallized 1g. of ()-2-dehydro-isoemetine as a dihydrobromide hydrate which melted,upon recrystallization from methanol, at 258- 260"; [u] =-107 (Q 1 inmethanol). U.V.-absorption maxima in ethanol at 82 m E=7,3G0. In orderto effect isolation of )-2-dehydro-emetine, the hydrobromic acidfiltrate was first concentrated to dryness, the residue then dissolvedin methanol and the soobtained solution then treated with ether untilturbidity. After being permitted to stand, the solution was filtered,yielding 2 g. of ()-2-dehydro-emetine-dihydrobromidehemihydrate, whichupon recrystallization from methanol/ether melted at 243245; [a] =94(c.=l in methanol). U.V.-absorption maxima in ethanol at k=282 me:7,300. The (-)-2-dehydro-emetine was obtained as a free base upondecomposition of the hemihydrate with dilute alkali, and melted, afterrecrystallization from isopropyl ether/ ether, at 9395;

awe-183 (c.=1 in methanol).

The same diastereoisomeric mixture was also obtained via catalytichydrogenation of ()-2-dehydro-O-methylpsychotrine, and it was separatedby the same procedure as described above.

EXAMPLE 2 10 g. of (+)-2-carbomethoxymethyl-3-ethyl-9,lO-dimethoxyl,4,6,7 tetrahydro llbH benzo[a]quinolizine (obtained according to theprocedure described in the above example) was dissolved in 500 ml. of10% aqueous acetic acid, 39.6 g. of mercuric acetate was then added tothis solution and the reaction mixture heated for 20 hours at 40, thenfiltered tree of the mercurous acetate formed, and the filtrate warmedat about 40 and hydrogen sulfide added over the course of 10 minutes.After the reaction mixture was cooled, mercurous sulfide was filteredoff, and the filtrate concentrated to about ml. in a water jet vacuum at40.

The concentrate was made alkaline by adding aqueous sodium hydroxide,'whereafter it was extracted with 200 ml. of chloroform. The chloroformextract was concentrated under reduced pressure, whereby 3.1 g. of aresidue were obtained, which upon recrystallization, gave 1.72 g. of2-carbo-methoxymethylidene-3ethyl-9,10-di methoxy-6,7-dihydro 2Hbenzo[a]quinolizine melting at 213-214"; U.V.-rnaxima in n/l00 alcoholicsodium hydroxide solution: 243, 293, 318, 389, mu (e:22,400, 11,470,16,900, 27,000). In the I.R.-spectrum the C O band was found at 6.02,u..

By reaction with ethanolic hydrogen chloride and addition of ether,2-carbomethoxymethyl-3-ethyl-9,l0-dimethoxy-6,7-dihydro-benzo[a]quinoliziniuntchloride was obtained; melting point: 204 (with decomposition):U.V.-maxima in rectified alcohol: 232 (shoulder), 269 (shoulder), 286and 365 my. (e=l1,900, 9,400, 13,700 and 12,300); C=O band in LR.spectrum at 5.79

1 g. of 2-carbomethoxymethyliden-3-ethyl 9,10-dimethoxy-6,7-dihydro-2H-benzo[alquinolizine was suspended in ml. ofmethanol, whereupon 0.5 got sodium borohydride was added to thesuspension in portions under slight cooling, so as to prevent thetemperature from rising above After 3 hours, the reaction mixture wasconcentrated under reduced pressure to about /3 of the original volume,the concentrate diluted with water and extracted with chloroform. Theresidue left upon concentration of the chloroform extract was convertedinto the hydrochloride by means of methanolic hydrogen chloride.Crystallization induced by the addition of aceton and ether, gave 0.65g. of rac. 2-carbomethoxymethyl 3 ethyl 1,4,6,7 tetrahydro 9,10-dimethoxy-l1bH-benzo[a]quinolizine hydrochloride. The latter can againbe split into the optical antipodes as described in Example 1.

EXAMPLE 3 2.0 g. of (+)2-carbomethoxymethyl-3ethyl-1,4,6,7- tetrahydro9,10 dimethoxy llbH benzo[a]quinolizine were dissolved in 300 ml. ofmethanol. By adding 32.5 g. of mercuric acetate there was formed asuspension which was heated under reflux and with stirring through 20hours. The suspension was filtered, hydrogen sulfide was introduced intothe filtrate and the mercurous sulfide formed was removed by filtration.

The residue obtained by concentration of the filtrate was converted tothe hydrochloride by means of methanolic hydrogen chloride, whereuponcrystallization was induced by adding ether. There were thus obtained4.05 g. of 2-carbomethoxymethyl-3-ethyl-6,7-dihydro- 9,l0-dimethoxy-benzo [a] quinolizinium chloride melting at 204 (withdecomposition). An additional quantity of 0.5 g. of this substance wasobtained from the mother wherein R is lower alkyl, and pharmaceuticallyacceptable acid addition salts thereof.

2. ()-2-dehydro-emetine -2-dehydroemetine.

substantially free from References Cited by the Examiner UNITED STATESPATENTS 2,877,226 5/1959 Brossi et al. 260-287 3,026,322 3/1962 Schock260286 3,045,020 7/1962 Battersby 260--288 3,048,591 8/1962 Lucas260*287 3,076,811 2/1963 Bartlett 260288 3,087,930 4/1963 Schut 260288FOREIGN PATENTS 821,332 10/1959 Great Britain.

OTHER REFERENCES Brossi et al., Helv. Chim. Acta, vol. 42. pp. 772-788,1515-1522 (1959).

Brossi et al., Experientia, vol. 18, pp. 211-12 (1962).

ALEX MAZEL, Primary Examiner.

NICHOLAS S. RIZZO, Examiner.

D. M. KERR, D. G. DAUS. Assistant Examiners.

1. A COMPOUND OF THE GROUP CONSISTING OF (-) COMPOUNDS, SUBSTANTIALLYFREE FROM THEIR DEXTRO ROTARY ISOMER, OF THE FORMULA